YTHDF2 promotes multiple myeloma cell proliferation via STAT5A/MAP2K2/p-ERK axis

Hua, Zhen; Wei, Rongfang; Guo, Mengjie; Lin, Zigen; Yu, Xichao; Li, Xinying; Gu, Chunyan; Yang, Ye

doi:10.1038/s41388-022-02191-3

Cited by 32 publications

(31 citation statements)

References 68 publications

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“…After the YTH domain binds the methylated RNA, multiple sites in the N-terminal region are involved in the recruitment of the CCR4-NOT complex which mediates the degradation of the mRNA polyadenine tail and triggers deadenylation-dependent mRNA decay. 8,11 YTHDF2 appears to be critically involved in a variety of human cancers, including hepatocellular carcinoma, 12,13 prostate cancer, 14,15 multiple myeloma, 16 and MYC-driven breast cancer, 17 as well as leukemic stem cell development and acute myeloid leukemia initiation and propagation. 18,19 Additionally, YTHDF2 seems to create, with the m 6 A writer methyltransferase-like 3−14 (METTL3−14), 20 a regulatory axis (renamed METTL3/YTHDF2 m 6 A axis 21 ) involved in the tumorigenesis of colorectal carcinoma, 22 bladder cancer, 21 and intrahepatic cholangiocarcinoma.…”

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confidence: 99%

Fragment Ligands of the m⁶A-RNA Reader YTHDF2

Nai

Nachawati

Zálešák

et al. 2022

ACS Med. Chem. Lett.

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We report 17 small-molecule ligands that compete with N6 -methyladenosine (m 6 A) for binding to the m 6 A-reader domain of YTHDF2 (YT521-B homology domain family 2). We determined their binding mode at high resolution by X-ray crystallography and quantified their affinity by a fluorescence-based binding assay. 6-Cyclopropyluracil and a pyrazolopyrimidine derivative have favorable ligand efficiencies of 0.47 and 0.38 kcal mol –1 per non-hydrogen atom, respectively. They represent useful starting points for hit optimization.

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confidence: 99%

Fragment Ligands of the m⁶A-RNA Reader YTHDF2

Nai

Nachawati

Zálešák

et al. 2022

ACS Med. Chem. Lett.

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“…It has been reported that ERK signaling pathway plays an important role in MM cell proliferation. For instance, Hua Z et al found that YTHDF2, an m6A reader, promoted MM cell proliferation via MAP2K2/ERK axis [ 19 ]. As a result, we intended to verify whether DAZAP1 promoted MM proliferation by activating the ERK signaling pathway.…”

Section: Resultsmentioning

confidence: 99%

DAZAP1 facilitates the alternative splicing of KITLG to promote multiple myeloma cell proliferation via ERK signaling pathway

Zhou

Huangfu

et al. 2022

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Multiple myeloma (MM) is an incurable plasma cell malignancy, in which alternativepre-mRNA splicing (AS) acts as one of the key transcriptome modifier. The Deleted in Azoospermia-Associated Protein 1 (DAZAP1) is a splicing factor that has been identified as an oncogene in multiple cancers, yet its role in MM proliferation remains unclear. We first analyzed MM clinical databases and found that MM patients with elevated DAZAP1 had a poor survival. Furthermore, we overexpressed DAZAP1 by lentiviral transfection and utilized siRNA silencing the expression of DAZAP1 in MM cells. DAZAP1 promoted MM cell proliferation in vitro and accelerated MM xenograft tumor growth in vivo. KEGG pathway enrichment analysis showed that ERK signaling pathway was activated in DAZAP1-OE MM cells. The analyses of RIP-seq and RIP-qPCR revealed that DAZAP1 activated alternative splicing of KIT proto-oncogene ligand (KITLG) mRNA. Further study validated that DAZAP1 increased ERK phosphorylation via modulating alternative splicing of KITLG mRNA to promote MM cell proliferation. In conclusion, we establish DAZAP1 as a tumor-promoting gene with therapeutic potential and provide mechanistic insights into targeting DAZAP1 as a new strategy for the diagnosis and treatment of MM.

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“…Consistent with our results, Ishibashi M et al reported that the ERK phosphorylation was decreased after knocking out CD229 in MM cells [ 36 ]. ERK is an important indicator of the action of RAS signaling pathway on cell proliferation [ 37 ]. In detail, for the two bands of (phosphorylated) ERK1 and ERK2 detected in Figures 3D , 3E , 4E , there was a slight difference in ERK1/ERK2 ratio between MM cell lines and in vivo tumor tissues, supporting their universal expression and critical regulatory role in cellular proliferation.…”

Section: Discussionmentioning

confidence: 99%

CD229 interacts with RASAL3 to activate RAS/ERK pathway in multiple myeloma proliferation

Lin

Tang

Cao

et al. 2022

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Multiple myeloma (MM) is an incurable plasma cell malignancy, while CAR-T therapy offersa new direction for the treatment of MM. Recently, signaling lymphocytic activation molecule family 3 (CD229), a cell surface immune receptor belonging to the signaling lymphocyte activating molecule family (SLAMF), is emerging as a CAR-T therapeutic target in MM. However, a clear role of CD229 in MM remains elusive. In this study, MM patients with elevated CD229 expression achieved poor prognosis by analyzing MM clinical databases. In addition, CD229 promoted MM cell proliferation in vitro as well as in xenograft mouse model in vivo.Mechanism study revealed that CD229 promoted MM cell proliferation by regulating the RAS/ERK signaling pathway. Further exploration employed co-immunoprecipitation coupled with mass spectrometry to identify RASAL3 as an important downstream protein of CD229. Additionally, we developed a co-culture method combined with the immunofluorescence assay to confirm that intercellular tyrosine phosphorylation mediated self-activation of CD229 to activate RAS/ERK signaling pathway via interacting with RASAL3. Taken together, these findings not only demonstrate the oncogenic role of CD229 in MM cell proliferation, but also illustrate the potential of CD229 as a promising therapeutic target for MM treatment.

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YTHDF2 promotes multiple myeloma cell proliferation via STAT5A/MAP2K2/p-ERK axis

Cited by 32 publications

References 68 publications

Fragment Ligands of the m⁶A-RNA Reader YTHDF2

Fragment Ligands of the m⁶A-RNA Reader YTHDF2

DAZAP1 facilitates the alternative splicing of KITLG to promote multiple myeloma cell proliferation via ERK signaling pathway

CD229 interacts with RASAL3 to activate RAS/ERK pathway in multiple myeloma proliferation

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YTHDF2 promotes multiple myeloma cell proliferation via STAT5A/MAP2K2/p-ERK axis

Cited by 32 publications

References 68 publications

Fragment Ligands of the m6A-RNA Reader YTHDF2

Fragment Ligands of the m6A-RNA Reader YTHDF2

DAZAP1 facilitates the alternative splicing of KITLG to promote multiple myeloma cell proliferation via ERK signaling pathway

CD229 interacts with RASAL3 to activate RAS/ERK pathway in multiple myeloma proliferation

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Fragment Ligands of the m⁶A-RNA Reader YTHDF2

Fragment Ligands of the m⁶A-RNA Reader YTHDF2